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March 19, 2009How to Tell If You're Poisoning Yourself With Fish

Read about more of the author's findings in Experimental Man, published by John Wiley and Sons.

When the halibut on my hook breaks the surface, writhing in a splash of seawater off the coast of Bolinas, California, I am thinking less of this fish's fate than of my own. Considering that I plan to kill and eat it, this might seem cruel. Yet inside the fat and muscle cells of this flat, odd-looking creature is a substance as poisonous to me as it is to him: methylmercury, the most common form of mercury that builds up inside people (and fish). At the right dose and duration of exposure, mercury can impair a person's memory, ability to learn, and behavior; it can also damage the heart and immune system. Even in small quantities, this heavy metal can cause birth defects in fetuses exposed in the womb and in breast-fed newborns whose mothers' milk is laced with it.

Scientists have assured me that one serving of halibut contains nowhere near a dosage that might cause harm. These are the same scientists, though, who admit that no one knows for sure what the threshold dose is that causes mercury to subtly poison cells in the brain and the liver, two organs where it tends to accumulate.

As frightening as that sounds, most of us were born with a defense against exposure to mercury, initiated by specific sequences of genetic code that cause most people to expel the metal in 30 to 40 days. Not everyone carries this natural resistance, however. A small minority of people carry a genetic mutation that apparently causes their cells to retain mercury for far longer---in rare cases up to 190 days---greatly increasing the chance for cellular damage.

Such genetic differences may explain why some people are more susceptible to mercury poisoning than others. This possibility is driving a nascent but growing effort among scientists to link the impact of mercury and other environmental factors (everything from pollutants and diet to the sun's ultraviolet rays) to the individual genetic proclivities that each of us is born with. "Toxicologists say that 'the dose makes the poison,'" says mercury expert Jane Hightower, who practices internal medicine in San Francisco, "but it's clear that some people are more sensitive to even small exposures than others."

For lack of a better term, I'll call this new science human envirogenomics, the fusing of environmental toxicology and genetics, two fields that until recently didn't interact much with each other. Yet researchers are finding that the interplay of the two makes us who we are and often determines whether we are healthy or sick. "Recent increases in chronic diseases like childhood asthma and autism cannot be due to major shifts in the human gene pool," says physician and geneticist Francis Collins, former director of the National Human Genome Research Institute. While acknowledging that changes in diagnostic criteria and heightened awareness may play a role, Collins says that much of the increase "must be due to changes in the environment, which may produce disease in genetically predisposed persons." One day, envirogenomics could provide clues to a person's sensitivity to environmental toxins (such as mercury) and the potential for damage based on that person's genes. Doctors might then better understand how to prevent such harm and how to treat patients exposed to deleterious chemicals.

Man versus mercury

The possible connection between mercury and my own DNA is why I'm now holding a quivering fishing rod on the bow of the Osprey, a weathered 24-foot trawler. I am conducting an investigation: testing my mercury levels before and after eating this fish---assuming I land him---and checking my personal genetic code to see if I am one of the lucky ones who seem to expel mercury quickly. At the same time, I can't help but wonder if this self-experiment is a sign that I am indeed sensitive to mercury and that it has already addled my brain. My hope is that these tests, plus discussions with experts around the world and a visit to an envirogeneticist in Maine, will help guide my decision when choosing between a large fish and, say, a bowl of pasta the next time I'm in a restaurant.

This exploration is the opening salvo in an extensive project in which I am treating myself as a human guinea pig, exploring four major new areas of personal testing: genes, environment, brain, and body. In essence I am aiming to answer two big, personal questions: How healthy am I at the very deepest level? And what can the seemingly endless profusion of new high-tech tests for various diseases and traits tell me about my health now and in the future?

My fish trial began a few days earlier when I gave up nine milliliters of blood and a cupful of pee to test my normal level of methylmercury---that is, the background level that I typically have in my body from living in 21st-century San Francisco. I'll give up another round of bodily fluids after eating today's catch for lunch and some store-bought swordfish for dinner.

In my "before" test for methylmercury, I registered a level of less than 4 µg/l (micrograms per liter), safely below the EPA threshold of 5.8 µg/l. This is a relief. But will my "after" level be higher?

Big fish are by far the most prevalent source of human mercury exposure, although researchers are exploring a number of other potential contributors. In 2008 a study at Boston University tested traditional herbal products manufactured in India and the United States and found lead, mercury, or arsenic in about one-fifth of them. Last year the FDA cited another potential source of harm for children and, through their mothers, fetuses: mercury contained in dental amalgams (those silvery fillings many of us have in our teeth). But the FDA has reserved judgment on health impacts for those of us who are not in early development and who do not have a medical condition making us more sensitive to mercury.

Methylmercury got into my fish from the coal-burning power plants that rim the northern Pacific Ocean, from the United States and Mexico to Japan and China. Expelled from tall stacks, mercury stays in the upper atmosphere until rain carries it down over the eastern Pacific, where it joins mercury from other sources as bacteria and other microorganisms transform it into methylmercury. After being absorbed by plankton, the mercury moves up the food chain: The plankton is eaten by small fish, which are then gobbled up by larger predators, each bigger animal accumulating more mercury with every meal. This process extends to the halibut that was now tiring and allowing me to reel it in as the Osprey's captain, Josh Churchman---a man in his fifties with a stubbly beard, graying hair, and a faded baseball cap---leaned far over a gunwale with a net.

The Osprey experiment is a follow-up to tests I had run to check my internal levels of 321 common pollutants, a process called a chemical body burden test. Scientists were able to detect traces of 163 of those compounds, including mercury, flame retardants, DDT, polychlorinated biphenyls (PCBs), and phthalates (a pervasive chemical that makes plastics soft and facilitates the addition of scents to shampoos, soaps, lotions, and deodorants). These pollutants have been detected everywhere from North Pole to South Pole and deep in every ocean. In animal tests and in accidental high-level exposures of humans, the chemicals have caused a range of damage and disease, including cancers, sterility, and birth defects. But the compounds normally show up in humans in amounts so small---parts per million, billion, even trillion---that scientists only recently developed the tools to detect them and are only now beginning to figure out how harmful they really are.

The tests showed that my levels are mostly average or slightly above average---another relief---with a few outliers such as DDT, a pesticide I was exposed to as a child growing up in eastern Kansas before its 1972 ban. Yet even my high level of DDT (and of DDE, a metabolite into which DDT breaks down in the environment) is still so minute that there has been no obvious harm to me.

This time, to check my genetic fortitude against such toxins I will use data from more than 1.5 million DNA markers I had tested for this project. The tests look for differences in the DNA nucleotides adenosine, thymine, guanine, and cytosine (A, T, G, and C---the letters of the genetic code) between one person and another, or between one group of people and another group. My results contain clues about what makes me genetically different from other people, such as blue versus brown eyes or a higher risk of getting diabetes or heart disease. Other DNA variations have been identified as conferring either protection from or susceptibility to chemical pollutants, though most of this work has been done with animals.

Lately, as envirogenomics has taken off, scientists have begun to test for genetic markers in humans who are most heavily exposed to pollutants, an effort that got a huge boost in 2006 when Congress approved the $40 million Genes, Environment, and Health Initiative, a program administered by the National Institutes of Health (NIH). Since then the initiative has funded a range of projects that investigate the effects of common toxins such as mercury, ozone, diesel exhaust, and pesticides---as well as other environmental influences, like diet and stress---on disease. The project is also sponsoring the development of new biomonitoring technologies, including better ways to track everything from psychological stress events and blood-cortisol levels to chemicals that dissipate quickly in the body, such as phthalates. "We're trying now to get relevant data on gene-environment interaction, to match exposure data with genetic data," says Brenda Weis, a former project manager for the Genes, Environment, and Health Initiative and now with the NIH Office of the Director. "The initiative is still new. No one knows exactly what we will find or how the data will come out."

Mercury moves up the food chain as plankton is eaten by small fish that are then gobbled up by larger fish, accumulating with every meal.

Meanwhile, at the Harvard School of Public Health, the similarly named Gene Environment Initiative is looking into how genes influence individuals' responses to mercury and selenium exposure. Selenium, another chemical that appears in fish, may mitigate some of the harmful effects of methylmercury, although this is debated. The Harvard project is tapping into medical information collected as part of the Nurses' Health Study and Health Professionals Follow-Up Study, which has tracked the health of 120,000 nurses in the Boston area and beyond since 1976. Dietary information is being gathered through questionnaires, mercury and selenium levels are being measured from toenail clippings, and genetic information is being acquired from blood and cheek swabs.

"Given the biologic relevance of mercury and selenium for human health and prior candidate gene studies demonstrating heritability, we anticipate discovery of major novel genetic regions that will greatly advance our understanding of the intersection between genes, dietary habits, and metabolism," the research team told Harvard Public Health Now, a publication of the Harvard School of Public Health.

The Big Fish Gorge

Back on the Osprey, Churchman scoops up my halibut in his net and drops it on the deck. After he stabs it and drains some of its blood, we fish for another hour or so amid whitecaps and a steady, chilly wind before heading back to Bolinas Harbor with a second halibut and a rockfish. As the little boat rides the waves and the twin outboard engines roar, I wonder what my tests will reveal about my susceptibility to mercury. Do I have a supergene deep inside me to fend off heavy metals?

A few days later I eat the halibut, which I have cooked with butter and basil, and then, for dinner, a swordfish steak grilled with lemon juice. The next morning I have another nine milli­leters of blood drawn, and I give up another container of urine.

Soon I receive my test results. With just those two meals, my mercury level has spiked from 4 µg/l to 13 µg/l, well over the EPA's recommended level of 5.8 µg/l. The results are even greater than when I ran the same test in 2006 with store-bought fish caught in the Pacific. That before-and-after test took me from 5 µg/l to 12 µg/l, a bump-up that prompted pediatrician and mercury expert Leo Trasande of the Mount Sinai School of Medicine in New York City to scold me for running a "fish gorge" experiment.

"No amount of mercury is really safe," Trasande says, although my results are far less significant than they would be for children or for women of childbearing age. Children have suffered losses in IQ at 5.8 µg/l, he cautions. After my first "gorge," Trasande had advised me not to repeat the experiment. I decided not to tell him that I had done it again.

My Genes and Mercury

Armed with my methylmercury data, I next go hunting to learn about the genes tucked into my cells that will or won't let me eat large fish in the future. The journey begins with an e-mail to Trasande, who tells me that as a clinician he is not aware of human genes that are impacted by mercury or of tests to determine a patient's genetic arsenal for coping with heavy metals. So I turn to animal toxicologists, who have identified several relevant genes in rodents, fish, dogs, dolphins, chickens, and fruit flies. Matthew Rand, a mercury toxicologist at the University of Vermont, has shown in fruit fly models that mercury binds to cells, including neurons, and interferes with signals being sent to the cells that control how they develop, replicate, and die.

Rand points me to a human study done by Karin Broberg, a molecular biologist at Lund University in Sweden who specializes in the toxic effects of metals. In 2008 her team published a study of 365 people that examined whether genetic variants influenced the elimination of total mercury in red blood cells. She concluded that mutant variations of two genes may impact a critical system in humans for flushing toxic metals, such as mercury, cadmium, and arsenic, out of the body.

Called GCLM and GSTP1, these genes help produce enzymes, such as glutathione-S-transferase, that maintain levels of glutathione, which plays a role in expelling metals from cells. Too little glutathione is one of the factors that cause metals to linger in cells, according to Broberg. "These findings suggest that GCLM polymorphisms [gene variants] that affect glutathione production also affect methylmercury retention," she wrote to me in an e-mail, "and that GSTP1 may play a role in conjugating [chemically joining] methylmercury with glutathione." Broberg's lab has identified specific locations within the DNA sequences for the GCLM and GSTP1 genes that, when mutated, may indicate a slower elimination of methylmercury from cells.

In gene-speak, Broberg's team found that individual letters in these genes are linked to how people retain or expel mercury. For instance, in one of Broberg's markers within the GSTP1 gene, people whose DNA contains an A have an elevated risk of retaining mercury longer. Those with two of them have an even higher risk.

I am startled to learn that I am double-A, the higher-risk variation. Broberg's study comes with a major caveat, however: This higher risk showed up only in those who consumed a high level of mercury. Another caution is that one marker considered in isolation does not take into account other genes and factors that might negate this singular result. As Rand says, "A much higher level of study with more subjects in the cohort would be required before concluding that a genotype [an individual's particular genetic variation] is a risk factor." Broberg also warns that these data are not yet ready to be used for evaluating an individual's sensitivity to mercury. Yet it suggests the sort of testing that may become common in the future.

Fortunately, there is a simple way for me to avoid a potential mercury overdose: no more halibut or swordfish, and no more fish gorging. According to the FDA and most experts, small fish and young fish contain less mercury and are probably safer to eat.

Unfortunately, eliminating the source isn't possible for most other pollutants that we breathe, eat, drink, and absorb through our skin whether we want to or not, in­cluding man-made chemicals such as phthalates and perfluoro­octanoic acids, which are found in Teflon and other widespread products. The basic chemistry of these and thousands of other manufactured compounds incorporated in everyday products do not appear in nature; they have entered our environment so recently that our genes, cells, brains, and bodies have not yet evolved mechanisms for coping with them.

Mutant variations of two genes may impact a critical system for flushing toxic metals, such as mercury, from the body.

"The glutathione enzyme and other anti­oxidants are good ones to study," says physician Mady Hornig of the Columbia University Mailman School of Public Health, whose lab studies the impact of toxins on the brain. "But I don't think anyone should rest easy if they come out normal" in genetic tests that look at just one or a few markers. "There are likely to be multiple genes that might contribute." Hornig says that the goal is to one day have a predictive genetic test that targets a person's potential for neural disorders, such as autism, on which environmental toxins are likely to impinge. "We are also looking for markers in the blood, such as proteomic markers," she says. Right now Hornig's lab is studying umbilical cord blood preserved at birth, looking for differences between the blood of children who became autistic and the blood of those who did not. The results will be published later this year.

The First Evirogenomic Profile

Near Acadia National Park in northeastern Maine, I feel the frigid wind blow off the ocean at the Mount Desert Island Biological Laboratory, a cluster of buildings enveloped in snow and surrounded by winter-bare trees. I have come here to find out more about my body's unique blend of environmental toxins and genetics from the scientists who run the Comparative Toxicogenomics Database (CTD), an online envirogenomics tool that cross-references thousands of chemicals, genes, and diseases. One of the coordinators of the NIH-funded project is Carolyn Mattingly, a tall, slender woman now wearing a thick overcoat and knit cap as she leads me through the snow to the building that houses the CTD staff.

Mattingly talks quietly and, like many scientists, responds to unfamiliar visitors as if interrupted from intensely absorbing work---which is fine, since her work is intensely absorbing. The researchers on the CTD team have examined 122,000 chemical-gene and chemical-protein interactions involving some 4,000 unique chemicals---including foods, vitamins, and naturally occurring compounds such as cholesterol. Along the way, they have looked at 13,500 genes in 200 species and their impact on 6,500 diseases. The team also integrates data from other sources on more than 60,000 chemicals.

Mattingly warns that this information as it applies to me, an individual, is incomplete. "We don't really understand how many of these chemicals work and interact at a very basic level in cells and in the body, so being able to know how they affect different people with different genetic variations is problematic at best," she says. Most researchers in the field agree. "The problem right now is that you don't have all of the information," says cancer biologist David Sherr of the Boston University School of Public Health, who studies the impact of chemicals like PCBs on breast cancer. "You have to understand the end point you're measuring. You can find out whether the substance is active, but at what dose, and is there an adverse response or not? You need to have a clear end point and a clear algorithm to a have a truly predictive model."

In a warm conference room overlooking a frozen cove, Mattingly opens her laptop and calls up my results for about 40 toxins that are present in my body at above-average levels: DDT, PCBs, flame retardants, metals, phthalates, and others. While I look on, she types "mercury" into the CTD search engine---a resource accessible to the public at ctd.mdibl.org---and up pops a menu offering links to peer-reviewed studies and media articles about genes and diseases tied to this pernicious metal. We find that there is information on 292 genes that have been tested for a response to mercury in 14 organisms, including mice, rats, dolphins, cows, ducks, and humans, with links to dozens of diseases from cancers to neurological disorders. Pulling up a grid with my results, Mattingly says that in this case, I came out normal in my genetic profile for gene variations associated with mercury sensitivity.

Next on the list is arsenic, which Mattingly studies in her own wet lab in a nearby building, testing its effects on zebra fish. The database lists more than 1,400 genes that are affected by arsenic in several animals, including humans. When I was tested for arsenic, my level was 12 parts per billion, safely under the official danger threshold of 23 ppb. This relatively low level of arsenic inside me was good news; Mattingly informs me that I have mutations in 22 of the 1,400 genes shown to interact with arsenic, including a variation in the ABCB1 gene that may inhibit my ability to expel the metal (and other toxins) from my body.

She calls up her analysis for PCBs, another class of chemicals detected inside me. Sherr and others have shown that PCBs, dioxins, and other organic pollutants seem to activate the aryl hydrocarbon receptor (AhR), which, among other things, contributes to cancer. One cause of cancer is healthy cells' growing out of control and losing their identity: They forget that they are programmed to be liver or heart cells and go rogue, not dying in the usual manner but instead continuing to replicate into more rogue cells. "In a normal cell, AhR causes the cell to grow if needed," Sherr says. "It's a basic part of life for many organisms. Certain chemicals make the AhR think it's being activated. The right kind of PCBs turn on the AhR, and it becomes a persistent signal that can contribute to cells' becoming cancerous." Sherr says that certain gene variations may be at work inside some people, putting them at higher risk for AhR activation by environmental chemicals. "It would help tremendously to know more about these genes and who is at risk," he says.

Chemicals interact with each other in a toxic soup inside our bodies and have an impact on possibly thousands of genes.

Mattingly checks on DDT, important given my high readings from my Kansas childhood. She finds close to 300 references to studies in the CTD, including a few on humans. A study in France in 2004 investigated the impact of various doses of DDT and three other pesticides from the same chemical family on two genes associated with a class of proteins known as cytochrome P450; the genes produce enzymes that metabolize a broad range of drugs and chemicals. This and other studies suggest that DDT and the other pesticides may alter not only specific genes but also pathways of genes that collectively control the immune system or other systems that can be altered by chemicals.

I'm not liking what I'm hearing, I tell Mattingly with a nervous laugh, but she reiterates that the data on human toxicity and the impact of pollutants on genes remain sketchy. As with other genetic studies linking diseases to DNA markers, her research tends to compare populations who have one variation of a genetic marker with those who have a different variation---a comparison that has limited application to individuals. Most genetic links need to be tested and confirmed in clinical settings with multiple patients; scientists also need to better understand how a given genetic marker causes sensitivity to a chemical. Neither the chemicals nor the genes work in isolation inside us. The chemicals interact with each other in a toxic soup in our bodies and may influence hundreds and possibly thousands of genes. "We have not had any way to test all of these interactions," Mattingly says. "The data are not robust; there are so many variables in multiple exposures. We can only look at footprints. There are some data on how groups of genes are impacted by one chemical, and other genes are affected by different chemicals. We are only beginning to look at this."

As snow fell outside and I began to squirm over what she was telling me, Mattingly kept describing other gene-chemical interactions. But I'll stop here, since much of the rest is equally unsettling and equally preliminary. Yet Mattingly and others insist this sort of analysis is on track to become more meaningful and perhaps useful for individuals in the next two or three years for some better-understood chemicals such as mercury and arsenic.

Without additional funding and attention, the uncertainties are likely to persist, says Christopher Austin, director of the NIH Chemical Genomics Center in Maryland. He is working with the Environmental Protection Agency and other groups to test the impact of pollutants on human and rodent cells. A much larger effort is needed---perhaps a Human Envirogenomics Project?---to really understand the implications of toxins and how they work on genes. Austin and others believe that the only way to create meaningful envirogenomics data is through a large prospective cohort study, collecting DNA samples and information about exposure to a variety of environmental factors from half a million to a million participants and following them for a number of years. This study would require a huge investment of time and effort and could cost as much as $3 billion (close to the cost of the Human Genome Project), according to a report issued in 2007 by the Secretary's Advisory Committee on Genetics, Health, and Society at the Department of Health and Human Services.

"A comprehensive study of this sort might tell us everything is OK," Sherr says, "though I suspect that it will tell us that some of these chemicals are not safe even at trace amounts."

Our Toxic World

I ponder all this one night while sitting on my roof in San Francisco, where I have a great view of the bay and the extraordinary hive of human activity in the city spread out below, much of it dependent on chemicals that have shown up inside me. Interstate 280 and the Bay Bridge swim with tides and eddies of automobiles; a partially shut-down power plant releases a steady white plume of effluents from a tall stack. Far to the north, a massive oil refinery and a storage depot spread across a hillside. Ships move up and down the bay, and jets roar overhead. Farther north is Bolinas and the Osprey, though I cannot see that far from here.

As a modern urbanite, I find this scene breathtaking and reassuring. I don't feel frightened or anxious, but I do feel an edge of unease, mostly because I lack the information to know what (if anything) all this human activity is doing to me, and to all those around me. Deep down, however, I suspect that there are trade-offs for our spectacular civilization that we have barely begun to understand, even as our technology is beginning to provide clues.

Read about more of the author's findings in Experimental Man, published by John Wiley and Sons.